Secondary Myelofibrosis Research Articles

Patient-specific comorbidities as prognostic variables for survival inmyelofibrosis.

Treatment decisions in primary myelofibrosis (PMF) are guided by numerous prognostic systems. Patient-specific comorbidities have influence on treatment-related survival and are considered in clinical contexts but have not been routinely incorporated into current prognostic models. We hypothesized that patient-specific comorbidities would inform prognosis and could be incorporated into a quantitative score. All patients with PMF or secondary myelofibrosis with available DNA and comprehensive electronic health record (EHR) data treated at Vanderbilt University Medical Center between 1995 and 2016 were identified within Vanderbilt's Synthetic Derivative and BioVU Biobank. We recapitulated established PMF risk scores (eg, Dynamic International Prognostic Scoring System [DIPSS], DIPSS plus, Genetics-Based Prognostic Scoring System, Mutation-Enhanced International Prognostic Scoring System 70+) and comorbidities through EHR chart extraction and next-generation sequencing on biobanked peripheral blood DNA. The impact of comorbidities was assessed via DIPSS-adjusted overall survival using Bonferroni correction. Comorbidities associated with inferior survival include renal failure/dysfunction (hazard ratio [HR], 4.3; 95% confidence interval [95% CI], 2.1-8.9; P= .0001), intracranial hemorrhage (HR, 28.7; 95% CI, 7.0-116.8; P= 2.83e-06), invasive fungal infection (HR, 41.2; 95% CI,7.2-235.2; P= 2.90e-05), and chronic encephalopathy (HR, 15.1; 95% CI, 3.8-59.4; P=.0001). The extended DIPSS model including all 4 significant comorbidities showed a significantly higher discriminating power (C-index 0.81; 95% CI, 0.78-0.84) than the original DIPSS model (C-index 0.73; 95% CI, 0.70-0.77). In summary, we repurposed an institutional biobank to identify and risk-classify an uncommon hematologic malignancy by established (eg, DIPSS) and other clinical and pathologic factors (eg, comorbidities) in an unbiased fashion. The inclusion of comorbidities into risk evaluation may augment prognostic capability of future genetics-based scoring systems.

Momelotinib (JAK1/JAK2/ACVR1 inhibitor): mechanism of action, clinical trial reports, and therapeutic prospects beyond myelofibrosis.

Janus kinase (JAK) 2 inhibitors are now part of the therapeutic armamentarium for primary and secondary myelofibrosis (MF). Patients with MF endure shortened survival and poor quality of life. Allogeneic stem cell transplantation (ASCT) is currently the only treatment modality in MF with the potential to cure the disease or prolong survival. By contrast, current drug therapy in MF targets quality of life and does not modify the natural history of the disease. The discovery of JAK2 and other JAK-STAT activating mutations (i.e., CALR and MPL) in myeloproliferative neoplasms, including MF, has facilitated the development of several JAK inhibitors that are not necessarily specific to the oncogenic mutations themselves but have proven effective in countering JAK-STAT signaling, resulting in suppression of inflammatory cytokines and myeloproliferation. This non-specific activity resulted in clinically favorable effects on constitutional symptoms and splenomegaly and, consequently, approval by the Food and Drug Administration (FDA) of three small molecule JAK inhibitors: ruxolitinib, fedratinib, and pacritinib. A fourth JAK inhibitor, momelotinib, is poised for FDA approval soon and has been shown to provide additional benefit in alleviating transfusion-dependent anemia in MF. The salutary effect of momelotinib on anemia has been attributed to inhibition of activin A receptor, type 1 (ACVR1) and recent information suggests a similar effect from pacritinib. ACRV1 mediates SMAD2/3 signaling which contributes to upregulation of hepcidin production and iron-restricted erythropoiesis. Targeting ACRV1 raises therapeutic prospects in other myeloid neoplasms associated with ineffective erythropoiesis, such as myelodysplastic syndromes with ring sideroblasts or SF3B1 mutation, especially those with co-expression of a JAK2 mutation and thrombocytosis.

CRP/Albumin Ratio and Glasgow Prognostic Score Provide Prognostic Information in Myelofibrosis Independently of MIPSS70-A Retrospective Study.

In myelofibrosis, the C-reactive protein (CRP)/albumin ratio (CAR) and the Glasgow Prognostic Score (GPS) add prognostic information independently of the Dynamic International Prognostic Scoring System (DIPSS). Their prognostic impact, if molecular aberrations are considered, is currently unknown. We performed a retrospective chart review of 108 MF patients (prefibrotic MF n = 30; primary MF n = 56; secondary MF n = 22; median follow-up 42 months). In MF, both a CAR > 0.347 and a GPS > 0 were associated with a shorter median overall survival (21 [95% CI 0-62] vs. 80 months [95% CI 57-103], p < 0.001 and 32 [95% CI 1-63] vs. 89 months [95% CI 65-113], p < 0.001). Both parameters retained their prognostic value after inclusion into a bivariate Cox regression model together with the dichotomized Mutation-Enhanced International Prognostic Scoring System (MIPSS)-70: CAR > 0.374 HR 3.53 [95% CI 1.36-9.17], p = 0.0095 and GPS > 0 HR 4.63 [95% CI 1.76-12.1], p = 0.0019. An analysis of serum samples from an independent cohort revealed a correlation of CRP with levels of interleukin-1β and albumin with TNF-α, and demonstrated that CRP was correlated to the variant allele frequency of the driver mutation, but not albumin. Albumin and CRP as parameters readily available in clinical routine at low costs deserve further evaluation as prognostic markers in MF, ideally by analyzing data from prospective and multi-institutional registries. Since both albumin and CRP levels reflect different aspects of MF-associated inflammation and metabolic changes, our study further highlights that combining both parameters seems potentially useful to improve prognostication in MF.

Machine Learning Improves Risk Stratification in Myelofibrosis: An Analysis of the Spanish Registry of Myelofibrosis.

Myelofibrosis (MF) is a myeloproliferative neoplasm (MPN) with heterogeneous clinical course. Allogeneic hematopoietic cell transplantation remains the only curative therapy, but its morbidity and mortality require careful candidate selection. Therefore, accurate disease risk prognostication is critical for treatment decision-making. We obtained registry data from patients diagnosed with MF in 60 Spanish institutions (N = 1386). These were randomly divided into a training set (80%) and a test set (20%). A machine learning (ML) technique (random forest) was used to model overall survival (OS) and leukemia-free survival (LFS) in the training set, and the results were validated in the test set. We derived the AIPSS-MF (Artificial Intelligence Prognostic Scoring System for Myelofibrosis) model, which was based on 8 clinical variables at diagnosis and achieved high accuracy in predicting OS (training set c-index, 0.750; test set c-index, 0.744) and LFS (training set c-index, 0.697; test set c-index, 0.703). No improvement was obtained with the inclusion of MPN driver mutations in the model. We were unable to adequately assess the potential benefit of including adverse cytogenetics or high-risk mutations due to the lack of these data in many patients. AIPSS-MF was superior to the IPSS regardless of MF subtype and age range and outperformed the MYSEC-PM in patients with secondary MF. In conclusion, we have developed a prediction model based exclusively on clinical variables that provides individualized prognostic estimates in patients with primary and secondary MF. The use of AIPSS-MF in combination with predictive models that incorporate genetic information may improve disease risk stratification.

The Sarawak Myelofibrosis (SaMy) experience: Demographics and outcome of myelofibrosis patients in Sarawak, Malaysia.

Introduction: Myelofibrosis is a rare disease. There is currently no published data reporting the demographics and outcome of myelofibrosis patients in Malaysia. We aimed to study the demographics, clinical characteristics, and outcome of our patients in Sarawak. Materials and methods: This non-interventional, retrospective, and multi-center study was conducted on secondary data of medical records collected at four Sarawak Public Hospitals. All adult myelofibrosis patients diagnosed between January 2001 and December 2021 were included. Results: A total of 63 patients (male 31) with myelofibrosis were included-47 (74.6%) primary and 16 (25.4%) secondary myelofibrosis. Eleven had antecedent polycythaemia vera, whereas five transformed from essential thrombocythaemia. The combined annual incidence rate was 0.182 per 100,000 population. The period prevalence per 100,000 population over the entire study duration was 2.502. The median age was 59.0 years (33.0-93.0). Majority had high-risk (34/63(54.0%)) and intermediate-2 risk disease (19/63(30.2%)). JAK2V617F mutation was identified in 52 patients (82.5%), followed by CALR mutation in 6 (9.5%) and negative for both mutations in 5 (7.9%). Hydroxyurea was used as first-line therapy in 41/63 (65.1%), followed by interferon (8/63(12.7%)) and ruxolitinib (4/63(6.3%)). Out of 46 patients who received second-line therapy, 18 (39.1%) were switched to ruxolitinib and 9 (19.6%) to interferon. The median age of survival for overall patients was 6.8 years. The use of ruxolitinib in myelofibrosis patients showed a better overall 5-year survival compared to the no ruxolitinib arm, despite no statistical significance (p = 0.34). Patients who had good performance status had lower hazard of death than patients who had poor performance status (high-risk (95% confidence intervals): 0.06(0.013-0.239), p < 0.001). Patients with intermediate risk disease had better overall survival compared to those in high-risk group (95% confidence intervals): 0.24(0.082-0.695), p = 0.009). Conclusion: This registry provides a real-world overview of myelofibrosis patients in our state and highlights the key insight into the unmet clinical need.

Erdheim-Chester disease associated with secondary myelofibrosis previously treated with ruxolitinib

Erdheim-Chester disease associated with secondary myelofibrosis previously treated with ruxolitinib

Thalidomide-induced sensory axonal polyneuropathy: A case report

Introduction: Several chemotherapeutic agents are currently available for the management of various malignancies; however, many are associated with adverse effects. A case of thalidomide- induced polyneuropathy is described below. Case Description: A 65year old man, with a history of secondary myelofibrosis in management with thalidomide, consulted for 5months of neuropathic pain and paresthesia in both hands. On physical examination, he presented hypoesthesia and hyperalgesia in both hands. In the electrodiagnostic studies (EDX) a sensory polyneuropathy of axonal type was concluded. Discussion: Chemotherapy-induced peripheral neuropathy (CIPN) is a side effect that occurs in up to 70% of patients. Symptomatology includes motor and sensitive deficit. EDX studies confirm diagnoses and characteristics. For the particular case of thalidomide involvement is mainly axonal. There is no standard treatment for CIPN, but several drugs can improve symptoms. Conclusions: CIPN is a frequent complication in patients managed with chemotherapy. The physiatrist is the ideal professional to provide a comprehensive approach to this entity, in order to improve the patient’s functionality.

PRIMARY MYELOPHYBROSIS: RECOGNIZING ONCET TO COMPLICATIONS

Myelofibrosis is the accumulation of scar tissue in the bone marrow so that blood cells cannot develop properly. Myeloproliferative disorders, myelofibrosis is classified into two, namely primary myelofibrosis and secondary myelofibrosis. In contrast to secondary myelofibrosis, primary myelofibrosis can occur without being preceded by myeloproliferative disorders or other diseases. In a 2013 meta-analysis study in Europe, the incidence of primary myelofibrosis (PMF) was around 0.3 per 100,000 per year. PMF may result from increased expression of inflammatory cytokines, lysyl oxidase, transforming growth factor-β, impaired megakaryocyte function, and aberrant JAK-STAT signaling. The most common clinical features found in patients with PMF are splenomegaly, hepatomegaly, fatigue, anemia, leukocytosis, and thrombocytosis. Currently the only treatment modality capable of prolonging survival or healing potential in MF is allogeneic hematopoietic stem cell transplantation (AHSCT) especially for high or very high risk patients.

Prediction of Survival and Prognosis Migration from Gold-Standard Scores in Myelofibrosis Patients Treated with Ruxolitinib Applying the RR6 Prognostic Model in a Monocentric Real-Life Setting.

The wide use of ruxolitinib, approved for treating primary and secondary myelofibrosis (MF), has revolutionized the landscape of these diseases. This molecule can reduce spleen volume and constitutional symptoms, guaranteeing patients a better quality of life and survival or even a valid bridge to bone marrow transplantation. Despite a rapid response within the first 3 to 6 months of treatment, some patients fail to achieve a significant benefit or lose early response. After ruxolitinib failure, new drugs are available to provide an additional therapeutic option for these patients. However, the correct timing point for deciding on a therapy shift is still an open challenge. Recently, a clinical prognostic score named RR6 (Response to Ruxolitinib after 6 months) was proposed to determine survival after 6 months of treatment with ruxolitinib in patients affected by MF. We applied this model to a cohort of consecutive patients treated at our center to validate the results obtained in terms of median overall survival (mOS): for the low-risk class, mOS was not reached (as in the training cohort); for the intermediate-risk, mOS was 52 months (95% CI 39-106); for the high-risk, it was 33 (95% 8.5-59). Moreover, in addition to the other studies present in the literature, we evaluated how the new RR6 score could better identify primary MF patients at high risk, with a slight or no agreement compared to DIPSS, contrary to what occurs in secondary MF. Thus, we were able to confirm the predictive power of the RR6 model in our series, which might be of help in guiding future therapeutic choices.

Novel Molecular Insights into Leukemic Evolution of Myeloproliferative Neoplasms: A Single Cell Perspective.

Myeloproliferative neoplasms (MPNs) are clonal disorders originated by the serial acquisition of somatic mutations in hematopoietic stem/progenitor cells. The major clinical entities are represented by polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF), that are caused by driver mutations affecting JAK2, MPL or CALR. Disease progression is related to molecular and clonal evolution. PV and ET can progress to secondary myelofibrosis (sMF) but can also evolve to secondary acute myeloid leukemia (sAML). PMF is associated with the highest frequency of leukemic transformation, which represents the main cause of death. sAML is associated with a dismal prognosis and clinical features that differ from those of de novo AML. The molecular landscape distinguishes sAML from de novo AML, since the most frequent hits involve TP53, epigenetic regulators, spliceosome modulators or signal transduction genes. Single cell genomic studies provide novel and accurate information about clonal architecture and mutation acquisition order, allowing the reconstruction of clonal dynamics and molecular events that accompany leukemic transformation. In this review, we examine our current understanding of the genomic heterogeneity in MPNs and how it affects disease progression and leukemic transformation. We focus on molecular events elicited by somatic mutations acquisition and discuss the emerging findings coming from single cell studies.

Pacritinib for myelofibrosis in adults with thrombocytopenia.

Myelofibrosis is a rare progressive cancer of the bone marrow that disrupts the normal production of healthy blood cells, leading to bone marrow failure. Patients with myelofibrosis and severe thrombocytopenia (platelet count below 50 × 109/L) have a wide range of unmet medical needs compared with those without thrombocytopenia. Usually, these patients have an increased disease burden, increased transfusion dependence, shorter overall survival, and limited treatment options. Pacritinib is a new oral kinase inhibitor specifically targeting Janus kinase 2 (JAK2), interleukin-1 receptor-associated kinase 1 (IRAK-1) and colony-stimulating factor 1 receptor (CSF-1R), and is indicated for the treatment of adults with moderate or high risk of primary or secondary myelofibrosis (post-polycythemia or post-primary thrombocytopenia) whose platelet count is less than 50 × 109/L. In this review, we introduce pacritinib and make a brief comparison of different JAK inhibitors in clinical application.

PACIFICA: A Randomized, Controlled Phase 3 Study of Pacritinib Versus Physician's Choice in Patients with Primary or Secondary Myelofibrosis and Severe Thrombocytopenia

Background: Myelofibrosis is a rare bone marrow disorder that is characterized by clonal proliferation of myeloid cells and bone marrow fibrosis. Myelofibrosis belongs to the group of BCR/ABL1 negative myeloproliferative neoplasms. Patients with myelofibrosis and severe thrombocytopenia (platelet counts <50x109/L) are generally older, with more advanced disease and increased risk of bleeding, higher rates of anemia and complex/unfavorable cytogenetics, and shortened overall survival compared to patients with higher platelet counts. So far, treatment options for patients with myelofibrosis and severe thrombocytopenia are limited due to the high incidence of treatment-related thrombocytopenia when other JAK inhibitors are used. Pacritinib is an oral JAK2/IRAK1/ACVR1 inhibitor with demonstrated clinical activity in myelofibrosis in two phase 3 studies and a phase 2 dose-finding study; all included patients with severe thrombocytopenia. The PACIFICA trial (NCT03165734) is designed to confirm efficacy and safety of pacritinib 200 mg twice daily vs physician's choice (P/C) therapy in patients with myelofibrosis and severe thrombocytopenia. Study Design: PACIFICA is a multinational, multicenter, randomized, controlled phase 3 trial of pacritinib vs P/C in adults with primary or secondary myelofibrosis with DIPSS intermediate- or high-risk disease, ECOG performance status 0-2, platelet counts <50 x 109/L, limited prior JAK2 inhibitor therapy (up to 270 days of low-dose ruxolitinib or up to 90 days of any JAK2 inhibitor), or JAK2 inhibitor naïve, and not candidates for stem cell transplant (Figure 1). Additional exclusion criteria include recent grade ≥2 cardiac or hemorrhagic events, left ventricular ejection fraction <50%, QTc >450 msec, or use of medications that increase risk of hemorrhage or QTc prolongation. Patients are randomized 2:1 to continuous pacritinib 200 mg twice daily or P/C (low-dose ruxolitinib [no more than 10 mg/day], danazol, corticosteroids, or hydroxyurea). Following regulatory feedback an amendment was initiated, and the study was updated to have co-primary endpoints involving both spleen volume reduction (SVR) and total symptom score (TSS). The co-primary endpoints are the proportion of patients achieving a ≥35% SVR and the proportion achieving a ≥50% reduction in modified TSS from baseline at week 24. To account for co-primary endpoints, the sample size was adjusted from 348 to 399 patients to provide 85% power to detect a difference between pacritinib and P/C. Secondary objectives include Patient Global Impression of Change response at week 24, overall survival, and safety. Tertiary endpoints include leukemia-free survival, hematologic improvement, fatigue improvement (based on PROMIS v.1.0 - Fatigue - Short Form 7a), changes in biomarkers and gene expression, and proportion of patients who experience a major adverse cardiac event (MACE). Given the US approval of pacritinib, PACIFICA is currently enrolling outside of the US at ~100 sites worldwide. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Machine Learning Improves Risk Stratification in Myelofibrosis: An Analysis of the Spanish Registry of Myelofibrosis

Purpose Myelofibrosis (MF) is a myeloproliferative neoplasm (MPN) with a heterogeneous clinical course. Allogeneic hematopoietic cell transplantation remains the only curative therapy, but its significant morbidity and mortality require careful candidate selection. Therefore, accurate disease risk prognostication is critical for treatment decision making. Patient and Methods Registry data were retrieved from patients diagnosed with MF between January 2000 and October 2021 in 59 Spanish institutions. A total of 1,386 patients were randomly divided into a training set (80% of the cohort) and a test set (20% of the cohort). A machine learning (ML) technique (random forests) was used to model overall survival in the training set and validate the results in the test set. Results The ML model, based on eight clinical variables determined at diagnosis, achieved high accuracy in predicting overall survival (training set c-index, 0.750; test set c-index, 0.744) and leukemia-free survival (training set c-index, 0.697; test set c-index, 0.703). We confirmed the superiority of the model compared with the IPSS in the prediction of survival at all time points evaluated (Figure 1A). Importantly, the model was superior to the IPSS regardless of age range (<60 or >60 years). We derived 4 equally distributed groups of patients from the model predictions, comprising 25% of patients each. By comparing this distribution with the IPSS risk groups, we observed that circa 50% of patients were reassigned to a different risk group by the ML algorithm (Figure 1B). Additionally, we did not observe any benefit from including MPN driver mutations or high-risk somatic mutations in the model. Furthermore, the ML model outperformed the prognostic accuracy of the MIPSS70 in primary MF and the MYSEC-PM in secondary MF. Conclusion The AIPSS-MF (Artificial Intelligence Prognostic Scoring System for Myelofibrosis) is based exclusively on clinical variables that are readily available in any healthcare facility. This simple model has demonstrated high prognostic accuracy for predicting survival in patients with primary and secondary MF, outperforming other well-established risk scoring systems. An interactive web calculator of this model can be accessed in the following link: https://geneticsoncohematology.com/MF/ Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Phase I Study of Ruxolitinib in Combination with Abemaciclib for Patients with Primary or Post-Polycythemia Vera/Essential Thrombocythemia Myelofibrosis

Introduction and preclinical rationale: Patients with primary and secondary myelofibrosis (MF) have a reduced life expectancy compared to age-matched controls. The prognosis of individual patients is defined by clinical, cytogenetic, and molecular disease characteristics. Several oral Janus Kinase (JAK)-1/2 inhibitors such as ruxolitinib are approved by the US FDA for the treatment of patients with intermediate or high-risk MF based on improvements in symptom burden and spleen volume reduction compared to physician choice of best available therapy. However, these inhibitors often have a limited duration of response, and survival in patients after ruxolitinib discontinuation is poor (median survival of 13 months). Novel mechanism-based therapies for patients with suboptimal response or progression on ruxolitinib are thus needed. Preclinical studies have demonstrated that JAK2 V617F mutations promote transition from G1 to S-phase of the cell cycle via increased expression of CDC25A. Notably, CDC25A expression has been shown to be upregulated in primary MPN patient samples. Additional cell cycle regulators such as CDK6 and Cyclin D have also been demonstrated to play a role in MPN pathogenesis and to drive myeloproliferation. Preclinical studies testing the combination of the CDK4/6 inhibitor ribociclib and ruxolitinib demonstrated reduction in spleen and liver size when compared to ruxolitinib alone in murine models, suggesting synergism (Rampal et al., Clinical Cancer Research 2021). Methods: Based on these promising preclinical data, we hypothesize that combining ruxolitinib with a CDK4/6 inhibitor could have synergistic effects in patients with primary or secondary MF who have an inadequate response to ruxolitinib monotherapy. In this multicenter, phase I dose-escalation trial we evaluate the safety of combination therapy with ruxolitinib and the CDK4/6 inhibitor abemaciclib. Patients with primary or secondary MF with intermediate-1/2 or high-risk disease by DIPSS who require treatment and had an inadequate response to ruxolitinib are eligible for enrollment. An inadequate response will be defined by (I) palpable splenomegaly ≥5 cm below the left costal margin at study entry AND/OR (II) active MPN symptoms [presence of one symptom score ≥5 or two symptom scores ≥3 using the screening MPN-SAF TSS (Emanuel at al. JCO 2012). (Table 1). This study follows a conventional "3+3” dose-escalation design, in which patients on a stable dose of ruxolitinib (10mg or 15mg BID) with sufficient baseline platelet and absolute neutrophil count will be treated with increasing doses of abemaciclib. The pre-study dose of ruxolitinib will be maintained to determine the maximum tolerated dose of the combination of ruxolitinib and abemaciclib (Figure 1). The primary endpoint of this study is to determine the safety and tolerability, and to identify the recommended phase II dose of abemaciclib in MF patients on a stable, standard dose of ruxolitinib. Secondary endpoints include overall response rate (defined as a composite of complete remission [CR], partial remission [PR], and clinical improvement [CI; defined as anemia, spleen or symptom response]), rates of CR, PR, and CI as well as progression-free survival (PFS), overall survival (OS), and duration of response (DOR) as defined in accordance with the modified 2013 consensus definitions proposed by the International Working Group - Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) and the European Leukemia Net (ELN). As part of this clinical trial several correlative studies are planned to identify biomarkers predictive of response to ruxolitinib and abemaciclib as well as mechanisms of resistance (e.g., MAP kinase pathway activation). These include evaluation of changes in variant allele fraction of driver mutations, gene expression profile, cell cycle, clonal architecture, cytokine profile, and bone marrow fibrosis, aiming to inform patient selection as well as other alternative combination therapies for future clinical trials. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Risk of Thrombosis in Myeloproliferative Neoplasms after Sars-Cov-2 Vaccination

Background SARS-CoV-2 infection has been associated with a poor prognosis in patients with Philadelphia-negative myeloproliferative neoplasms (MPN).(Passamonti et al. Lancet Haematol. 2020;7(10):e737-e745). Nevertheless, given the concerns about SARS-CoV-2 vaccine-associated thrombosis (Pavord et al. N Engl J Med 2021;385(18):1680-1689) and the well-known thrombotic risk associated with MPN (De Stefano et al. Leukemia 2016;30(10):2032-2038), patients had frequently vaccine-hesitancy and some of them even refused to be vaccinated. Methods To estimate the potential risk of thrombosis associated with SARS-CoV-2 vaccination in MPN, we evaluated 335 consecutive MPN patients vaccinated against SARS-CoV-2 with at least one dose. Proportional hazard Cox model for multiple failures was used to compare the risk of thrombotic complications according to vaccine exposure (treated as time-dependent covariate), and results of these models were reported in terms of Hazard Ratio (HR) for vaccine exposure vs non-exposure periods, together with its 95% Confidence Interval (95%CI). The exposure period was defined for each patient from the date of any SARS-CoV-2 vaccine dose till 30 days after; the non-exposure period included for each patient the six months before the first dose and the period beyond 30 days after each dose till last follow-up (see Figure 1A). To take into account time between diagnosis and enter date, left-truncation was applied. Results Starting from January 2021 we enrolled 335 MPN patients, including 99 affected with PV, 176 affected with ET, 49 affected with primary or secondary myelofibrosis and 11 affected with MPN unclassifiable. Median age was 55 years (range 15-88); 153 (46%) were males and 182 (54%) were females. Considering the mutational status, 252 patients (75.2%) were JAK2 V617F-mutated, 55 patients (16.4%) were CALR-mutated, 6 patients (1.8%) were MPL-mutated and 22 patients (6.6%) were triple negative. Seventy out of 335 patients (20.9%) were not receiving cytoreduction at the time of vaccination; the remaining 265 (79.1%) were under cytoreductive treatment (226 with hydroxyurea, 22 with ruxolitinib, 13 with interferon, 4 with busulfan). A previous history of thrombosis was reported in 100/335 (0.3%). Almost all patients received at least two doses of vaccination against SARS-CoV-2 (331/335, 98.8%); 75% of patients (224 of 335) received also the third dose. In most patients (320/335, 95.5%) the first two doses consisted of mRNA-based vaccines; in only 15 out of 335 (4.5%) the first two doses consisted of adenovirus-vectored vaccines. In all cases the third vaccination was performed with mRNA-based vaccines. Thrombotic complications included only major thrombosis. The risk of thrombosis in the exposure period did not significantly differ from the risk of thrombosis in the non-exposure period (HR=0.8; 95%CI 0.04-15.4, P 0.866), as shown in Figure 1B. No case of cerebral venous thrombosis was reported in the post-vaccine period. Conclusions Although these results need to be confirmed in larger studies, these data deliver an important message to the clinical community: SARS-CoV-2 vaccines do not increase the risk of thrombosis in MPN patients; thus, it is pivotal for health care professional to vaccinate the highest number of MPN patients, reassuring them regarding thrombotic complications. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Mylox-1: An Open-Label, Phase IIa Study of the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Oral LOXL2 Inhibitor, GB2064, in Myelofibrosis

Background: GB2064 is a high-affinity, selective, pseudo-irreversible, small-molecule inhibitor of LOXL2, a secreted glycoprotein that crosslinks extracellular matrix collagens and elastin which contributes to stiffness and loss of function of fibrotic organs. GB2064 is being developed as an oral treatment for myelofibrosis (MF), a rare myeloproliferative disease with high morbidity and mortality. Janus kinase (JAK) inhibitor therapy has brought significant advancements in the treatment of MF, but a significant proportion of patients would eventually discontinue treatment, predominantly due to the development of cytopenias (Kyukendall et al.,Ann Hematol. 2018). Thus, a substantial unmet need to develop well-tolerated disease-modifying treatments that reduce bone marrow fibrosis to improve haematological parameters, splenomegaly, symptom burden and quality of life remains. Aims: To assess the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and clinical effects of oral GB2064 (1000 mg twice daily [BID]), which was administered to participants with primary or secondary myelofibrosis (PMF/SMF) for 9 months. Methods: Open-label study in 16 adult participants diagnosed with PMF or SMF in accordance with World Health Organization diagnostic criteria (Barbui et al., Blood Cancer 2018; Cruz et al.,Expert Rev Hematol. 2020), who are not taking a JAK inhibitor and therefore are likely to be refractory, intolerant or ineligible for such inhibitors; participants had Eastern Cooperative Oncology Group performance status 0-2, and the clinical laboratory parameters were within appropriate limits per protocol. Primary endpoint is safety and tolerability. Safety and tolerability, PK, PD and appropriate MF-specific assessments will take place at all visits except Day 7, Day 15 and Month 4 when only safety and tolerability will be assessed (Fig A). Bone marrow biopsies, magnetic resonance imaging of spleen and quality of life measures, MPN-10 and EQ-5D-5L are performed at prespecified timepoints within the protocol. Exploratory endpoints include LOXL2 binding assay in the circulation, relationships between PK plasma exposure, PD markers, and markers of clinical activity, fibrosis and inflammation biomarkers (YKL-40, PAI-1, PDGF, CCN2, collagen formation and degradation neoepitopes). The study is not formally powered. Participants who derive benefit may continue therapy for an additional 3 years (Fig B). Results: At least half of the intended participants have been enrolled and are on GB2064 treatment as of June 2022. One participant successfully completed the study in May 2022 and moved to the extension phase. GB2064 was detected in bone marrow biopsies at concentrations close to those in the plasma and demonstrated LOXL2 target engagement in the systemic compartment using a LOXL2 binding assay in plasma. No significant safety concerns were observed at a dose of 1000 mg BID to date. Conclusions: MYLOX-1 is designed to explore the safety and clinical effects of GB2064, a novel small-molecule LOXL-2 inhibitor, addressing bone marrow fibrosis as a main element of MF, with the aim to decrease extramedullary haematopoiesis and improve haematological parameters, symptom burden and the quality of life for patients with MF. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Pulmonary Engraftment Syndrome: A Unique Complication of Allogeneic Hematopoietic Cell Transplantation for Myelofibrosis

Background: In myelofibrosis patients undergoing alloHCT, we have observed a pulmonary infiltrate predominant engraftment syndrome with or without hypoxemia. Therefore, we sought to characterize this unique syndrome further and determine its association with pre-HCT patient and disease characteristics and determine its impact on HCT outcome. Methods: From our HCT database, we identified 83 patients with primary/secondary myelofibrosis who underwent alloHCT at our institution from 2015 to 2020 at City of Hope. Data on patient demographics, disease characteristics, disease status at HCT, mutations, HCT-related variables and outcome measures were collected from patient medical records. Pulmonary ES (PES) was defined as the combination of new onset of pulmonary opacities in the absence of infection, fluid overload, and cardiac dysfunction with or without hypoxemia occurring between ten to twenty days after stem cell infusion. All statistical analysis was performed using SAS statistical software. Results: Among the 83 patients included in this study, 49% had PMF, and 51% had secondary MF. Their median age was 62 years (range 55-68) and the majority of the patients were male (n=53,64%). The JAK2 V617F mutation was detected in 65% (n=54) of patients. Prior to an alloHCT, 61% (n= 51) had received treatment with ruxolitinib. The median spleen size was 20 cm (range 16-23 cm). Graft source for allo-HCT was matched unrelated donor (MUD) in 54%, followed by matched related donor (MRD) in 23%, mis-matched unrelated (MMUD) in 12%, and Haplo-identical donor in 11%. Mobilized peripheral blood stem cells were used as a graft source in 97.6% of donors. Most patients (94%) received a non-myeloablative/reduced-intensity conditioning regimen. Tacrolimus/sirolimus was used in more than half of the patients (57.8%, n=48). The median CD34+ and CD3 cells were infused at a median 6x10^6 cells/kg (range: 2.49 - 12.96) and 2.21x10^8 cells/kg (range: 0.25 - 4.90) respectively. The median time for neutrophil engraftment was 20.0 days. 25 patients (30%) had new pulmonary infiltrates between days 10 and 20 of HCT. 22% (n=18) met the criteria for PES. Nine of those patients (50%) required an ICU admission. A majority (n=12) of patients with PES required systemic steroid therapy. Demographic factors and transplant characteristics did not reveal any risk factors for PES. Pre-HCT CT scan chest was reported as normal in 87% of patients. There was no association between abnormal CT chest before HCT and occurrence of pulmonary ES (OR 0.29, 95% CI 0.01 - 2.52, p 0.42). Pulmonary artery hypertension (defined as PASP ≥35 mmHg) was observed in 61 patients (77%) in this cohort. PAH was associated with increased risk of PES with an odds ratio 3.68 (95% CI 1.13,12; P=0.04). An abnormal pulmonary function test (PFT), defined as FEV1<80%, FEV1/FVC<70%, and DLCO< 80 were found in 19%, 23% and 72% patients during pre-HCT testing, respectively. No association was seen between PFT abnormalities and the occurrence of PES (FEV1 p=0.25 95% CI 2.60 0.50-13.32, FEV1/FVC p=1.00, 95% CI 0.84 0.08-5.40, DLCO p=0.74 95% CI 0.18-4.10). 12-month OS and 2-yr OS was 65% and 63%, respectively. Patients who experienced PES had no difference in overall survival (OS) and Non-Relapse Mortality (NRM) in comparison to those who did not have PES (HR;1.93, 95% CI 0.94-3.97, P 0.074 and HR 1.63; 95% CI 0.70- 3.83, P 0.26, respectively). There was a significant difference in ICU stay by PES (50% vs 17%, p=0.01). But length of ICU stays were not significantly different by PES (median 18 days vs 5 days, p = 0.13). Patients with median PASP>35 and pre-HCT spleen size >20 cm had worse OS in multivariate analysis (HR 2.58, 95% CI 1.24-5.40, P<0.001, and HR 4.14, 95% CI 1.83-9.36, p<0.001), while pre-HCT median PASP of greater or equal with 35 mmHg was associate with worse NRM (HR 2.42, 95% CI 1.04-5.62, p 0.040) Conclusion: In this study, we describe a novel variation of engraftment syndrome consisting of predominantly pulmonary infiltrates, occurring around the time of neutrophil engraftment in patients undergoing alloHCT for MF. Although this syndrome was not associated with decreased overall survival or increased non-relapse mortality, it was associated with significant morbidity and requires early recognition to initiate corticosteroid therapy. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

The Combination of Navitoclax and Ruxolitinib in JAK Inhibitor-Naïve Patients with Myelofibrosis Mediates Responses Suggestive of Disease Modification

Background: Myelofibrosis (MF) is a myeloproliferative neoplasm associated with splenomegaly, high symptom burden, bone marrow fibrosis (BMF), and poor prognosis. The Janus kinase inhibitor (JAKi) ruxolitinib is the current standard of care for patients with MF. It improves splenomegaly and disease symptoms with limited impact on disease biology, highlighting an unmet medical need in MF. Driver mutations of JAK2, CALR, and MPL are key to the pathogenesis of MF. Reduction in variant allele frequency (VAF) of driver mutations and reversal of BMF are suggestive of disease modification (Pemmaraju, Cancer, 2022). Additionally, mutations in ASXL1, EZH2, SRSF2, IDH1/2, and U2AF1 p.Q157 are classified as high molecular risk (HMR) mutations associated with a worse prognosis (Arber et al., Blood, 2016). We previously demonstrated evidence of disease modification independent of HMR mutations by adding navitoclax to ruxolitinib in patients with suboptimal responses to ruxolitinib monotherapy (Pemmaraju, Lancet Oncology, 2022). Herein, we investigated whether the type of MF and risk (e.g., age, Dynamic International Prognostic Scoring System [DIPSS], and HMR) correlated with clinical outcomes and responses suggestive of disease modification (e.g., VAF reduction and improvement in BMF) among JAKi treatment-naïve patients with MF treated with the combination of navitoclax and ruxolitinib. Methods: Cohort-3 of the phase-2 multicenter REFINE study (NCT03222609) enrolled JAKi treatment-naïve patients with MF. Enrolled patients had primary or secondary MF with splenomegaly (DIPSS ≥ Intermediate-1) and did not receive prior JAK-2 therapy or bromodomain and extra terminal motif (BET) inhibitors. Patients initiated navitoclax at 100 mg QD or 200 mg QD if baseline platelet count was ≤ 150 × 109/L or > 150 × 109/L, respectively. Ruxolitinib was given BID with starting dose based on baseline platelet count per local label. The primary endpoint was spleen volume reduction of ≥ 35% (SVR35) from baseline at week 24, assessed by MRI conducted by central review. Key secondary and exploratory endpoints evaluated in this analysis were a reduction in BMF obtained from BM biopsies by local evaluation and a reduction in VAF for the driver gene mutations (JAK2V617, CALR, or MPL), respectively. Driver gene VAF and HMR mutations were determined in whole blood with the 50-gene Focus Myeloid next-generation sequencing panel (Interspace Pharma Solutions, Morrisville, NC, USA). Results: As of Feb 07, 2022, all enrolled patients (N = 32) treated with navitoclax and ruxolitinib were evaluable for biomarker analysis. The median duration of follow-up was 6.1 months (range, 1.9 – 18.6); median age was 69 years (range, 44 – 83), and median spleen volume was 1889.08 cm3 (range, 645.6 – 7339.6). At baseline, 22 (69%) patients had JAK2, 6 (19%) had CALR, and 3 (9%) had MPL mutations. One (3%) patient was triple negative. Nineteen (59%) patients had HMR mutations. SVR35 at week 24 was observed in all subgroups known to confer poor prognosis, including age (≥75 years, 50% [n = 4/8]), high DIPSS score (Intermediate-2, 63% [n = 12/19]; high, 33% [n = 1/3]), and HMR mutations (47% [n = 9/19]; Figure). BMF grade improvement was evaluable in 26/32 (81%) patients, of which 9/26 (35%) achieved ≥ 1-grade improvement at any time during treatment with a median time-to-improvement of 12.3 weeks (range, 12.1 – 24.1). Complete resolution of BMF was observed in 2/9 (22%) patients. The baseline BMF grades of these patients were 2 and 3. BMF ≥ 1-grade improvement was achieved by 7/13 (54%) patients with HMR mutations and 2/13 (15%) without HMR mutations. Reduction in driver gene JAK2V617 mutation VAF > 20% from baseline at week 12 or 24 was observed in 14/28 (50%) patients, and 5/14 (36%) patients achieved > 50% VAF reduction from baseline. There were no differences in > 20% VAF reductions from baseline to week 12 or 24 between those with or without HMR mutations (7/15 [47%] versus 7/13 [54%], respectively). Conclusions: Among JAKi treatment-naïve patients with MF, the combination of navitoclax and ruxolitinib reduced splenomegaly in several high-risk groups known to confer poor prognosis. Reductions in BMF and VAF were independent of HMR mutations. The reduction in BMF and VAF for the driver mutation JAK2V617 is encouraging and suggestive of evidence of disease modification with the combination of navitoclax and ruxolitinib. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Preliminary Data from the Phase I/II Study of TP-3654, a Selective Oral PIM1 Kinase Inhibitor, in Patients with Myelofibrosis Previously Treated with or Ineligible for JAK Inhibitor Therapy

Introduction: Myelofibrosis (MF) is characterized by bone marrow (BM) fibrosis, ineffective hematopoiesis, splenomegaly, and debilitating symptoms. Expression of PIM-1 is significantly upregulated in MF hematopoietic cells, supporting exploration of PIM-1 as a potential therapeutic target in MF. TP-3654 is a highly selective oral investigational PIM-1 kinase inhibitor. When administered alone and in combination with ruxolitinib, TP-3654 reduced spleen size and BM fibrosis in JAK2V617F and MPLW515L murine MF models (Dutta, 2021). In addition, TP-3654 decreased cytokine response genes and serum TGF-b in progenitor cells and JAK2V617F mice, respectively. TP-3654 showed less hematopoietic inhibition than Janus kinase (JAK) inhibitors (ruxolitinib, pacritinib and momelotinib) in in vitro human megakaryocyte and erythrocyte cell colony formation. Methods: This Phase I/II study evaluates the safety and efficacy of TP-3654 monotherapy in patients with MF (NCT04176198). Key eligibility criteria include primary or secondary MF; intermediate or high-risk MF per DIPSS; previously treated with or ineligible for JAK inhibitor treatment; grade ≥2 BM fibrosis; platelet count ≥25x109/L; absolute neutrophil count ≥1x109/L; splenomegaly; and ≥2 measurable symptoms. The study aims to identify the maximum tolerated dose and/or recommended Phase II dose using a Bayesian logistic regression model (BLRM) with overdose control, and to assess clinical activity (spleen volume reduction [SVR], total symptom score [TSS] improvement, and BM fibrosis reduction), safety, pharmacokinetic, and pharmacodynamic markers in peripheral blood and BM biopsies. Results: As of 11 July 2022, 8 patients were enrolled across 5 dose levels in the dose escalation phase. At baseline, median age was 70 years (range, 61 to 77), median spleen volume was 2370 cm3 (range, 1189 to 4407), median total symptom score was 19 (range, 4 to 62), median platelet count was 120 x109/L (range 68 to 237), median hemoglobin was 10.1 g/dL (range, 5.9 to 13.7), and two patients were transfusion-dependent. All patients had received prior treatment with at least one JAK inhibitor. Median duration of prior JAK inhibitor treatment was 35 weeks (range, 13 to 269). Six patients had JAK2V16F mutation, 2 patients had CALR mutation. The median duration of TP-3654 treatment was 21 weeks (range, 1 to 45). No dose-limiting toxicities occurred. Treatment-related adverse events (TRAEs) occurring in >20% of patients included mild to moderate nausea, vomiting, and diarrhea. Grade ≥ 3 TRAEs included only 1 case of vomiting. No hematological TRAEs were reported. No discontinuation due to AE occurred. SVR was observed in 5 out of 6 evaluable patients (median best change -14%, range -3.2% to -35%) (Figure 1). Symptom improvement was observed in 5 out of 6 evaluable patients (median best change -70%, range -32 to -100%). A panel of cytokines were evaluated in plasma samples obtained at baseline and during TP-3654 treatment. Reductions in cytokines (TGF-b, IL-18, VEGF, RANTES, MMP-9, and TIMP-1) were observed after TP-3654 treatment (Figure 2). Patients with higher cytokine reductions correlated with higher reduction in total symptom score. Enrollment is ongoing, updated data will be presented. Conclusions: The preliminary clinical data in dose escalation show: 1) encouraging signs of clinical activity in spleen volume reduction, symptom improvement, and cytokine reduction with TP-3654 monotherapy in patients previously treated with JAK inhibitors, 2) TP-3654 is well tolerated with limited myelosuppressive adverse events. The non-clinical findings and preliminary clinical safety/efficacy data support accelerated development and assessment of TP-3654 as the optimal partner for combination with JAK inhibitors. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

The Use of Fedratinib for Myelofibrosis As a Potential Bridge to Hematopoietic Stem Cell Transplantation after Ruxolitinib Failure: Real-World Assessment of Treatment Characteristics and Spleen, Symptom, and Hematologic Response

Introduction: Janus kinase (JAK) inhibitors provide therapeutic benefits and symptom control in patients with myelofibrosis (MF) regardless of line of therapy. However, their use as a treatment pathway to hematopoietic stem cell transplantation (HSCT), the only curative option for patients with MF, is poorly understood. In August 2019, the JAK inhibitor fedratinib (FEDR) became the second treatment to be approved in the US for treatment of intermediate- or high-risk primary or secondary MF. We previously observed that 18% (12/67) of patients discontinued FEDR following failure of treatment with ruxolitinib (RUX) to undergo HSCT (Mascarenhas J, et al. Blood 2021;138(Suppl 1):1980). Here we describe patient characteristics, treatment characteristics, spleen and symptom changes, and outcomes following discontinuation of FEDR to undergo HSCT among real-world patients prescribed FEDR after treatment with RUX. Methods: Treating physicians from community oncology practices in the US selected eligible patients and completed electronic case report forms from February to March 2021. Eligible patients were adults with intermediate- or high-risk MF, who were treated with RUX and subsequently initiated FEDR on or after August 16, 2019, with ≥ 90 days of follow-up, and who had completed ≥ 1 cycle of FEDR and had discontinued FEDR prior to data cutoff to undergo HSCT. Physicians abstracted demographic and disease characteristics, RUX and FEDR treatment characteristics, spleen size, symptoms derived from the Myelofibrosis Symptom Assessment Form version 4.0 (MFSAF v.4.0), platelet count, hemoglobin (Hb), white blood cell (WBC) count, peripheral blasts, disease transformation, and death. Descriptive analyses characterized patient demographic and clinical characteristics, as well as disease transformation and death. Mean spleen size (length determined by palpation), symptom count, platelet count, Hb, WBC count, and mean proportion of peripheral blasts at FEDR initiation versus 3 months post-FEDR initiation were compared via paired 2-sided t-tests; P values < 0.05 were considered statistically significant. Results: A total of 12 patients underwent HSCT; 58% were male. At FEDR initiation, mean age was 56 years (interquartile range [IQR], 50-63), 42% of patients had ECOG performance status ≥ 2, and the mean Charlson Comorbidity Index score was 0.3 (standard deviation [SD], 0.6). Median RUX treatment duration prior to FEDR was 10.3 months (IQR, 6.3-25.4), and median time from RUX failure to RUX discontinuation was 23 days (IQR, 7-39). Median time from RUX failure to FEDR initiation was 1.1 months (IQR, 0.9-1.9). All patients received starting FEDR doses of 400 mg once daily; median FEDR treatment duration was 5.3 months (IQR, 4.1-7.9). From FEDR initiation to 3 months post-FEDR initiation, patients showed a statistically significant reduction in mean spleen size and mean number of symptoms (Table). Median follow-up after FEDR initiation was 9.4 months (IQR, 4.4-13.5). Disease transformation to acute myeloid leukemia occurred in 1 patient. No deaths were recorded as of the data cutoff in March 2021. Conclusions: This is the first real-world evidence on baseline characteristics and outcomes of patients with intermediate- or high-risk MF receiving FEDR after RUX failure, as a potential bridge to HSCT. Based on this dataset, HSCT following FEDR appears to be an effective and safe treatment option to consider. Larger prospective studies in patients treated with FEDR prior to HSCT should be conducted to determine efficacy and safety in this setting. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal